Derivatives of 2,4-oxazolidinedione



Patented May 23, 1944 Roger W. Stoukhton, Ferguson, Mo., assignor toMallinckrodt Chemical Works, St. Louis, Mo.,'

\ a corporation of Missouri N Drawing.

Application January 14,; 1 942., Serial No. 426,783 I 4 Claims, (Cl.260-307) Thisinventionmelates to new derivatives of 2,4-,oxazolidinedione, and with regard to certain more specific features,to such derivatives which represent; substitutions in the 5-position bytwo alkyl radicals,- one of which contains at least three carbon atoms.

This application is a continuation-impart of my copending application.Serial No. 318,321, filed February 10, 1940.

Among the several objects of may be noted the provision of new chemicalcompounds which are -5-substituted. derivatives of 2,4-oxazolidinedione,and their alkali and. alkaline earth metal salts, useful as therapeuticsand,

the provision of' new intermediates for the preparation of thesecompounds. Other objects willbe in part-obvious and in part pointed outhereinafter.

The invention accordingly comprises the elements and combinations ofelements, the proporthis invention 0.25'molof dry urea is dissolved in100ml. of a" A mixture of 0.2 mol of ethylaHl-blltYl-mmethyl-a-hydroxyacetate (prepared, for example, by thehydrolysis and subsequent esterification of the cyanohydrinofmethyl-n-butyl ketone, 01', as described in Example 5, post), with 2.5normal solution of sodium'ethylate in abso lute alcohol. 'The mixture isheated under a reflux for from ten to twelve hours, after which thealcohol is distilled off under reduced pressure, and-the residuedissolved in a minimum amount of cold water. "Theunreacted ester is thenextracted with ether, the extracted aqueous solution is then acidified,and an' oil separates out. This oil is purifiedby distillation underreduced pressure. The product is a colorless oil boiling tions thereof,and features of composition, which will be exemplified in the substancesand products hereinafter described, and the scope .ot the application ofwhich will be=indicated in the following.claims.. q U a .The compoundsincluded in this inventionmay be represente d by the following type.formula:

cmcmomcm magi bflmeearea the-following manner:

between 1 i8andI51 C. under 3.5 mm, pressure. It is' slightly soluble inwater, and easily soluble in alcohol, ethe'nbenzene and petroleum ether.,7 ,-Eaample 2 5-methyl-5=n-amyl 2;4 oxazolidinedione is 010-" tained bysubstituting for the ester in Example 1, ethyl'a'-n'-amyl-u-methyl-whydroxyacetate. The product-is obtained as a waxysolid-melting at 25C;"to'a colorless oil,'which boils at 158 to 160 C.under l mm; pressure. It is very slightly soluble in" water and easilysoluble in alcohol, ether, benzeneand petroleum ether.

I ExampleS. 5-ethyl 5-isoamyl 2,4-oxazolidinedi0ne is ob tainedbysubs'tituting forthe ester in'Example 1. ethylu-ethyl-bc-isoamyl-a-hydroxyacetate. The product is obtained as'acolorless oil boiling from 150-to 153 C. under 2.5 mm. pressure. It isinsoluble in waterfbut easily soluble in alcohol, ether, benzene andpetroleum ether.

Example 4 5.-n j-amyl- 5-ethyl.--2,4-oxazolidinedione is prepared asfollows: Sodium metal (6.2 g.) was dissolved .in dry methylalcohol ('70ml.) in a threenecked, 500. ml. flask, fitted with a reflux condenservand a mercury sealed stirrer. To the cooled solution wasadded a solutionof a-ethylaahYdIlOXY ,enanthamidel46 g.) in diethyl carbonate (32s.)over a ten minute period. The reaction mixture was refluxed for sixhours. After the alcohol had been distilled off at atmospheric pressure,the cooled residue was dissolved in icewater (300 ml.)- and theresultant yellowish, solution extracted-with three ml. portions ofisopropyl ether. The'aqueous solution ,was next treated with. about l g.of bonecoal, and

' a Claisen flask under reduced pressure.

' is condensed with urea to prepare. the oxazolidinedione compoundsdescribed above may be. conveniently obtained by the hydrolysis andsubsequent esterification of the cyanohydrin of the correspondingdialkylketone. In some instances.

was then heated by means of a water bath for placed 9.2 g. of magnesiumturnings, 5 ml. of ethyl bromide and 25 ml. of anhydrous ether. Acrystal of iodine was added, and after the reaction had started, 250 ml.of ether were added. A mixture of 43 g. of ethyl-a-keto-a-methylcaproate(prepared as described in the following example (and 38 g. of ethylbromide. was then added dro-pwise through the separatory funnel, at sucha rate as to cause the ether to reflux gently. This required about sixhours. The flask onehour, and then allowed to stand over night at. roomtemperature. The next morning the reactionmixture was, cooled anddecomposed by the; slow addition of 150 ml. of 6N sulfuric acid, and anequal volume of water. The ethereal layer fwas separated, washed withsodium carbonate however, it may be more convenient to obtain thematerial for the urea condensation in other manners. I

Example 5 Ethyl a-n-butyl-a-methyl a hydroxyacetatewas prepared asfollows; in a one-liter threenecked flask, fitted with a mechanicalstirrer and dropping funnel, are placed a solution of 26 g. (0.5 mol) ofsodium cyanide (techincal cyanegg) in '75 ml. of water, and 50 g. (0.5mol) of n-butyl methyl ketone. The flask 'Was cooled .in an ice bath,stirred vigorously, and 130 ml. of

a saturated solution of sodium bisulfite was added to the mixture over aperiod of one and a. half hours. Stirring was continued for a half hourafter the addition of the bisulfite had been completed. The cyanohydrinlayer was separated and dissolved in 200 ml. of absolute alcohol, towhich 5 ml. of water had been added. This mixture was saturated with drygaseous hydrogen chloride, and refluxed fortwenty hours. From time totime the ammonium chloride which separated was fi-ltered off. to preventbumping. The excess alcohol was then removed by distillation from thesteam bath. and the residue poured onto cracked ice. The resulting oilwastaken up in ether, washed witha sodium carbonate solution, anddistilled. A-small amount of free acid was recovered from the carbonatewashings. The ethyl ester so obtained" had a boiling point of. 100 to101 C. under 25 mm. pressure. The corresponding acid,namely,.a-n-butyl-a-methyl-ahydroxyacetic acid, obtained by hydrolyzingthe ester, had a. melting point of '33"C'. and a boiling point under 5'mm. pressure'of 127 to 12.9 C.

The ester product so: obtained may then. be converted by the procedureoutlined above to 5-methyl-5-n-butyl-2,4-oxazolidinedione, by' reactionwith urea. 1

Example 6 Ethyl s-n-amyl- -methyl a hydroxyacetate was prepared bysubstituting methyl n-amyl ketone for the methyl n-butyl ketone inExample 5. The ester so obtained boils between 112 and 113 C. under 23mm. pressure. The corresponding acid has a. melting point of 44 to 45 C.and a boiling point of 139 to 140 C. under 6 mm. pressure. The esterproduct may be converted into 5-methyl-5-n-amyl-2,4-oxazolidinedione bythe method outlined above.

:Example 2 Ethyl e-ethyl-d isoamyl u-hydroxya-cetate is preparedasfoll'ows: Into a'three-liter, three.. necked flask fitted"wit'h amechanical stirrer, reflux condenser and dropping funnel, were solution,and distilled. The fraction boiling at to C. under 20 mm. pressure wascollected. This crude product was stirred with 100 ml. of a saturatedsodium bisulfite solution, and allowed to stand for twenty-four hours.At the end of this time, the sodium bisulfiteaddition product of theunchanged keto ester was removed '1 by filtration, and the hydroxy acidester taken .up in benzene. This was further purified by carefulrectification'through an efiicient fractionating column. This method ofpurification leaves a little keto acid present, but it can be removed byhydrolyzing the ester, and recrystallizing the acid from petroleum etheror-dilute methanol, if desired. The acid melts at 69 to 70 C. and boilswithout decomposition at 121 to 125 C. under a pressure of 3 mm. Thepure ester boils at 114 to 115 C. under a pressure of 20 mm. The esterproduct 's o obtained may be reacted with urea to form5-ethyl-5-isoamyl-2,4-oxazolidinedione.

Example 8 Ethyl a-keto-6-methylcaproate is prepared as follows: In athree-liter, three-necked flask fitted with a mechanical stirrer, refluxcondenser and dropping funnel, were placed- 146 g. I (1 mol) ofethyl-oxalate dissolved in 500 ml. of anhydrous ether. The flask wascooled in anice salt bath, the stirrer started, and one molecularequivalent of isoamyl'magnesium bromide prepared from 27 g. of magnesiumand 151 g. of isoamyl bromide in 400 m1. of dry ether was added over aperiod of five hours. During this time the temperature was maintainedbetween -5 and -10 C. After the addition of the Grignard reagent wascompleted, the mixture was stirred for two hours longer and allowed tostand over night at room temperature. The flask was again cooled and thereaction mixture decomposed by slowly adding 300 ml. of 6N sulfuricacid, with vigorous stirring. The ether layer was separated, washed Awith a sodium carbonate solution, and distilled through an efiicientfractionating column. The boiling point of the ester was 109 to 110C.under 20 mm. pressure. The corresponding semicarbazone had a meltingpoint of to 161 C.

Example 9 tained between C. and C. The oil which had separated wascollected and to it was added with stirring and cooling concentratedsulfuric acid (130 ml.) which had been previously diluted with water (13ml.) and cooled. The addition required 25 minutes, and the temperaturewas maintained between C. and -5 C. Stirring was continued for one hourat 0 C. and the reaction mixture allowed to stand over night at roomtemperature. The next morning the solution was poured onto cracked ice(600 g.) and the oil layer taken up in ether. The ether solution waswashed with sodium carbonate and finally with water. The product wasfinally distilled under reduced pressure. The fraction boiling at131-134 C. was collected and amounted to 54 g. (50%) of a pale-yellowoil. This oil solidified on standing, and melted at 4345 C. Purw-ethyl-a-hydroxy enanthamide could be obtained by recrystallizationfrom chloroform and petroleum ether mixture, and melted at 49- 50 C.

All of the oxazolidinedione compounds described above behave asmono-basic acids, and form salts with alkali and alkaline earth metalhydroxides or carbonates. These salts may be conveniently preparedmerely by reacting an equivalent of the alkali or alkaline earth metalhydroxide or carbonate with the oxazolidinedione.

The S-substituted 2,4-oxazolidinedione com pounds prepared in accordancewith the present invention have especially valuable therapeuticproperties. Moreover, it has been found that the efiicient dose fortheir therapeutic efiect is far less than a lethally toxic dose. Theseproducts may be used in any of the forms usually employed, for example,their solutions may be administered orally or by subcutaneous orintramuscular injection.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As many changes could be made in the above substances and productswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in 9- limiting sense.

I claim:

1. A compound selected from the group consisting of5-methyl-5-n-butyl-2,4-oxazolidinedione,5-methyl-5-n-amyl-2,4-oxazolidinedione, 5-ethyl-5-isoamyl-2,4-oxazolidinedione, and5-ethy1-5-n-amy1-2,4-oxazolidinedione, said compound being prepared foruse as a therapeutic.

2. fi-methyl-5-n-amyl-2,4-oxazolidinedione.

3. 5-ethyl-5-isoamyl-2,4-oxazolidinedione.

4. 5-ethyl-5-n-amyl-2,4-oxazolidinedione.

ROGER W. STOUGHTON.

